Process for the preparation of 16alpha-bromo-and 16alpha-iodopregnanes



United States Patent ()fi" 3,189,622 Patented. June 15, 1965 ice No Drawing. Filed Dec. 11, 1963, Ser. No. 329,864 7 Claims. (Cl. 260-397 .4)

The present invention relates to a novel process for the preparation of steroid compounds and is more particularly concerned with the preparation of l6u-bromoand 16aiodopregnanes.

The process consists in the isomerization of 16p3-bromoor respectively 1618-iodo steroids of the pregnane series to l6c-bromo or respectively 16u-i0d0 steroids of the pregnane series with the aid of Raney nickel in high yields. 1613-iodoand l6B-brom0 steroids of the pregnane series are well known and have been generally prepared by subjecting a 16,17a-oxido-pregnane compound to the action of hydrobromic or respectively hydroiodic acid. Under these conditions a l6 8-bromo- (or iodo)-17u-hydroxypregnane compound is obtained.

The terms pregnane and compound of the pregnane series are herein used generically for compounds having the basic structure below and having frequently substituents, particularly: in positions 3, 11 and 20, hydroxy, acyloxy and oxo groups; in position 6, methyl and fluoro; in position 9; fluoro; and double bonds in positions 1,2, 4,5, 5,6, 6,7; and the like. Other substituents such as methyl, hydroxy, and acyloxy in positions 2, 4, 7, 12, 14 or 15 may also be present, as they do not interfere with the isomerization process.

The main object of this invention is to provide a high yield method for the production of 16a-halo-17a-hydroxypregnanes, since the biological activity of l6a-halo-l7u hydroxypregnanes is far superior to those of the l6 3-halo- 17a-hydroxypregnanes. Thus, the 16,8-fluoro derivatives of hydrocortisone, 9a-fiuoro-hydrocortisone acetate and 9a-fiuoropreduisolone exhibit lower anti-inflammatory activity than the parent compounds [Moreland et al., Chem. and ind. 1034 (1960)]. Gther tests have shown that the anti-inflammatory activity (Granuloma Pouch Test) of 9a,lofi-ditluoroprednisolone acetate is about equal to hydrocortisone (:1) while the a-isomer, 9a,16a-difiuoroprednisone acetate, possesses 77 times the anti-inflammatory activity of hydrocortisone. Beyler et 21.. [J. Org. Chem. 21, 572 (1956)] report 16,8-chlorocortisone to be inactive as an anti-inflammatory agent. On the'other hand the ISa-fluoro compounds disclosed in US. Patents 2,915,434, 2,915,435 and 3,033,747 are all very active compounds. Similarly, Belgian Patent 623,567 shows the high 7 activity of 16a-chloroprednisolones. Although 16;?-

bromo-cortisone acetate is known [Julian et al., I. Am. Chem. Soc. 77, 4601 1955)], no remarkable activity thereof has been acknowledged.

Consequently 16,8-halo steroids found applications only as intermediates. No method has been heretofore known to convert 16B-halopregnanes to 16a-halopregnanes, which latter compounds are of significant biological activity.

The novel process of the present invention is therefore useful for the preparation and in the preparation of valuable therapeutically and biologically active 16u-bromo- (or'iodo)-l7a-hydroxypregnanes which possess enhanced anti-inflammatory, anti-arthritic, anti-allergic and progestational activities. These compounds are particularly superior to the l6 8-epimers when used as intermediates in reactions requiring basic medias, since the l6/3-bromoor -16,8-iodo-17a-hydroxypregnaues form with bases the corresponding 16a(17u)-oxidopregnane with elimination of hydrogen halide. The 16a-halo-17u-hydroxypregnanes do not undergothis elimination reaction.

The starting materials, 16fi-bromoand IGfi-iOdO-l'lochydroxypregnanes, are either known in the art, or described in this application. They are generally produced by the opening of a l6 x(-17cc)-0Xld0 bond of a pregnane compound with hydrogen bromide or, respectively, with hydrogen iodide. The 16a(17u)-oxidopregnane itself is produced by the reaction of a ld-pregnane compound with a peroxide, e.g., hydrogen peroxide, t-butyl hydroperoxide (US. Patent 3,014,905), with a peracid,-e.g., peracetic acid, performic acid, perbenzoic acid, and the like.

In carrying out the process of the present invention the selected 16,8-bromoor respectively l6fi-iodo-l7u-hydroxypregnane is dissolved in an organic solvent and treated with activated nickel, e.g. Raney nickel, preferably, but not necessarily, under exclusion of oxygen, in an inert gas, e.g. a nitrogen atmosphere. The organic solvents used in this process are generally alcohols, ethers, organic acids and chlorinated organic compounds such as methanol ethanol, and propanol, isopropanol, t-butanol, tetrahydrofuran, diethylether, diisopropylether, ethyl acetate, butyl acetate, methyl propionate, chloroform, methylene chloride, chlorobenzene, and the like. In the preferred embodiment of this invention methanol is used as a solvent.

The reaction time and temperature may be varied Widely. The optimum conditions depend somewhat on the nature of the substrate: thus, at room temperature the reaction is best carried out between 1 and 48 hours while at the boiling point of solvents the time required for the reaction to be completed is between 2 minutes and minutes. I The amount of steroid to Raney nickel is usually varied between 0.5 part to 3 parts of Raney nickel per part of steroid to giveoptimum yield. However, ratios of 0.1 to 10 parts of Raney nickel to 1 part of steroid are operative.

The active nickel employed is generally commercially available Raney-active nickel catalyst and may be used as is or preferably may be neutralized with dilute aqueous acetic acid and washed with methanol or treated prior to use with hydrogen iodide or hydrogen bromide in aqueous methanol and washed with methanol or treated with hydrogen bromide in aqueous methanol and washed with methanol. Satisfactory high results were obtained, particularly when the Raney nickel was first neutralized with dilute aqueous acetic acid and washed with methanol. Nickel-chromium catalyst was also useful for carrying out the isomerization, but other Raney metals, cobalt, iron or copper, were less effective.

In a typical experiment a methanolic solution of one part of 16,8-bromoor 16p-iodo-l7u-hydroxypregnane is heated under reflux and stirred with about an equal weight of Raney nickel for a period of 1 hour while the oxygen is displaced from the system with nitrogen gas. Thereafter the reaction mixture is cooled, filtered and the filtrate evaporated to dryness to give a residue. The product is recovered by direct crystallization of the above residue from organic solvents such as methanol, ethanol, Skellysolve B hexanes, ethyl acetate,

' pregnen20-one was as follows:

' the desire d material, The total yield was 8 g mixtures, benzene, ether, and isopropyl "ether. tion and isolation may alsobe carriedout by chromatography'over Elorisil anhydrous magnesium silicate and alumina prior to crystallization or recrystallization f Example 1.-16 t-bn6m -3B,1'7ui-dihydmxy 6- meZHyZJ-p egnen-ZO-One A suspension (if-160517 odido 6 methylpregnenolone (US. Patent 2,878,247) 7 g.) ini20.ml. of methyle'ne heptane mixtures, octane Purifica chloride was cooled to 0 C. and thereupon treated with ;17 .2 ml. of ether containing 12.5 8* g. of hydrogen'bromide foraperiod of 2 minutes.,-After 5 minutes a s'olid'began 1 to separate and after standing overnight at roomter'npe'ra ture the solid was filtered off andwashedwith'fmethylene chloride to give 10.58. g. (85.6%) of'lrifi-bromo-ilfifladihydroxy-6-rnethyl5-pregnen-20 one; A .secondc-rop of of dioxane, purified over anhydrous alumina, were stirred at room temperature (22-25 C) while 20 mi of 47% aqueous hydroiodicfaoid was addedduring a period of 3 minutes. The mixture was thereupon'stirredovernight in a nitrogen atmosphere. Thereafter 125 ml. rwat r was added slowly over a period .of 30 minutes under continuous stirring and seeding, After,afurther'20rminutes,

'the' solids which separated wre filteredoif 'andzwashed on the filter. with water. These solids .weredried invacuo at 40 C. to-give,l2.6 g: of'material melting; at 172 C.-"

0.39. g. (3.2%) could be obtained by evaporating the mother liquors and 'triturating the, thus-.obtained solids with methylene chloride-.1 a

Y 'Recrystallizationof the thus-obtained li6fi-bromo- 3fl,

l7ot-dihydroxy-6-methyl 5-pregnen -one from methanol and subsequentlyfrom ethyl acetate gave prisms of pure 1 6B -;br'o'm0.-3 ,8, l7a dihydroxy-6-rnethyI-S-pregnen-ZO-one ofmelting point 207 2 1(? C. With"de oomposition and rotation [e1 5 -7 in'dioxane, 0.9.molar. solution, having' 1 an analysis as follows;

Recrystallizing' this material from ethyl acetate containing enough methanol to dissolve the starting material gave a first crop of 8.6 g.;of 16fleiodo-3/3,l7et dihydroxy-i methyl j-pre'gnen-ZO-on'e of rnelting point 179? C. with decomposition and a second-crop of 1.2g. ,of; melting point 177 Cgwith decomposition. 7

Recrystallization of this 16B-iOdO-3fi,17ct-(lil1YdYQXy-6-;, methyl-5-pregnen-20-one: from methylene dichloride' and; Skellysolve B 'hexanes' gave 'pure 16B-iodo-3fi ,-17p-dihy droxy-6-methyl-5-pregnen 20-one of melting point 185 A-ndlysisfCalcd. for s er. of, 62.11;H, 7.82

Br, 18.79. Found: C,6l.83; H,'7.65; Br, 18.71. K'suspension of 1 g; of finely powdered 16,8-bromo- 3B,l7oz-dihydroxy-6-methyl-5-pregnen-20-one in'ZO m1. of

methanol was treated'with 3.5. g; of Raney nickeL; The

Raney: nickel had previonsly'been' treated'w'ith'a few drops of 'agueousfhydrogen'jbromide in methanol boiled and. washed with methanol; The reaction mixture .thus obtained was refluxed in a nitrogen'atmosphere withagita- .tion for25 minutes. After cooling, needles separated,

which'were redissolved by' adding methylene chloride, the solutionwas filtered, thus; removing the nickel and the thus-obtained'filtrate concentratedto a small volume.

To this filtrate was added a little waterwhereupon needles separated weighing 0.47 g. and consisting of 16a-bromo- 3B,l7u-dihydroxy-6 methyl j 5 pregnen-ZO-one of melting point'220.-222; C. These needles'w ere further purified V by recrystallization from methylene chloride-methanol to give pure '16 -bromo-3 8,l7a-dihydroxy-6-rnethyl=5-preghen-ZO-one; of melting point 22'5 '227 Cfand rotation [11] 37- in both chloroform and dioxane." Theanalysis 6 7 methyl 5-- An zlyszs- Calcd. for C H QBr: C, 62.11; 'H, 7.82; Br, 'l8.;79, Found; C,'62.20;'H,'7.87; Br, 1 8.48.. In the same manner 10 got 16fi-bromo-3'B,17a,dihydroxy-6-methyl-5-pregnen-20-one were refluxedwith' 5 g. of Raney= nickel (pretreated with; acetic acid' and then boiled with methanol) in ml. of metanol under stirring for a period of 27 minutes. The mixture was the'reupon concentrated toabout /3 of the volume by removing th condenser, then cooledto'roomtemperature over a a period of 1 hour, filtered and washed with a very little methanol and the solids extracted with'4-00 ml. of 10% methanol'in methylene chloride. "The nickel was removed by filtration. Concentration of the filtrate and extracts afteraddiiton of methanol and'further concentration gave 5.10 g. of 16u-brorno-3fi,17edihydroxy-6-methyl-5-preg- 5 was diluted. with methanol, concentrated and furtherfdi 186 C. withdecomposition and having'a rotationlof mb s chloroform, T analysis of thislmatenialis as follows: .7 I.

a. Analysis.' Calcd. for c,,u,,o,1 c, 33; ngmgr 26. 87. 7 Found: C,'55.68;,H, 7.07; I, 27.05. I L

A 'mixture'of .1. 'gxer -16e iodo-3glfi -dihydroxygee I methyI-S regnen-ZO- one, 10 ml. of methanoland 33 g.

' of Raney nic kel'(previouslyboiled in'methanolwith 47% hydrogen iodide,. .decanted.land washed with methanol) 7 a was refluxedffor a period of. 15 minutes,then cooled, di-,

luted with methyleneichloride and filtered. The filtrate luted with water givinga precipitate which was recrystallized from methylene;chloride+Skellysolve B hexanes to nen-ZO-one of melting p0int230 233 C., rotation [6:1 41 inichloroformandhaw'n'g anianalysis as follows: Analysis.-Calcd. forC H IO -LC, 55.93; H, 7.04; 1, 26 .8 7. .'Found:jC;'55.58; H, 6. 96; 1,26 .79. Example 3.--lfia-br 0mo-3B,1Zu,21-trihydr1oxy-5- i preg zen-2 0 o ne-3,Zi-diqcetate A solution of 16ml7 -oxidor3pllgdiacetoxyipreguen- 20-one. [5 .g. prepared as'described by'P. L. Julian et al.,

I, Am.Chem. ,Soc., 72, 5145 (1950)] in 17 ml. of glacial .50' acetic acid was treated atroom ternperature with 2.92 'g.,

or hydrogen bromide in acetic acid and after 10 minutesf .was treated with ml; "of water to precipitatecrude 16,6-

. .bromo-3,8,l7u,21-trihydroxy-5-pregnen-20-one 3,21-diacetate. This product wasrecovered from the reaction mix ture by filtration. The crude material was recrystallized from methylene chloride-SkellysolveB 'hexanes =to give 16/3 brorn'o -SB,17a,2l-trihydroxy-5 pregnen-20-one 3,21

diacetate ofzmel'ting'point 1695171 0., which upon re- 7 crystallizaiton from Skellysolve B hexanes have pu e 16B- nen-20-one of melting point 222-225 C, which by'addi- .4

' tional'purificatio'nthroug'h crystallization from methylene chloride-methanol, gave 'l6a-bromo-3fi,l7a dihydroxy-6 methyl-S-pregnen-Ztleon of melting'point 225-227 1C, as

1 a'bove. a p f' 5 1 I a Concentration of the mother liquors gave asecond crop;

methyI S-pregnen-ZQ- ne' and a third crop of. 0.45. g. of

7 and-havingan analysis as follows;

. uponconcentrated tofabout 5 ml. andIrefiuxedjfurthen for 4 hoilrs. The mixture was ,then concentratedj'to a Memo-3 5,17q,2l-trihydnoxy-pregnen-ZO-Onei3,2l diace-. tate ofmelting fpoint 17-0 172? 6., rotation d ,24",'

, A mixture of; 0.50 g.;of thus-obtained: 16/3-bromoa 3B,l7iz,2l trihydroxy 5-pregnen-3-one 3,2l-diacetate', 012-5 g. 'of Raney nickel andZO ml. of methanolwas he ated under 'refluxfor a few minutes. Themixturewas thereismaller. volume, cooled, filtered and'the" filtrate-discarded,

' then the solids remaini'ng'on'the filterwere extracted with methylene fchloride and methanol These exttactswqe theneva'porated to, give a soliiwhicli was repeatedly crystallized from methanol to give pure l6u bromo 3e,170:,21-trihydroxy;5-pregnen-20 one 3,21'-diacetjat e of a melting point 220222 C., rotation [11],; 36 in chloroform and having an analysis as follows:

Analysis.Calcd. for C H O Br: C, 58.71; H, 6.89;

Br. 15.62. Found: C, 58.97; H, 7.01; Br, 15.74.

Example 4 In the same manner given in the preceding Examples 1-3, other 16a(17a)-oxidopregnanes can be treated with hydrogen bromide to give the corresponding 16,8-bromo- 17a-pregnane and isomerized with Raney nickel in methanol, ethanol, tetrahydrofuran, ethylether or other organic solvents to give the corresponding 16e-bromo-l7a-hydroxypregnanes. In this manner there were obtained from:

(a) 3a-acetoxy-l6a(17a)-oxidopregnane-11,20 dione [Percy Julian, Recent Progress in Hormone Research, vol. VI, Academic Press, Inc., publishers, New York, 1951, page 200] first 3u-acetoxy-16fi-bromo-17a-hydroxypregnane-11,20-dione, and then 3er-acetoXy-16u-bromo- 17 a-hydroxypregnane-l 1,20-dione.

(b) 3fihydIOXY-160c(17a)-OXid0 4 pregnene-11,20- dione [Percy Julian, Recent Progress in Hormone Research, vol. VI, Academic Press, Inc., publishers, New York, 1951, page 200] first BB-hydroxy-16fl-bromo-17uhydroXy-4-pregnene-11,20-dione, and then 318-hydroxy- 16e-bromo-17m-hydroXy-4-pregnene-1 1,20-dione.

(c) 16a(17a)-oxido-21-acetoxy-4 pregnene 3,20-dione [ibid., page 201] first 16fi-bromo-17u-hydroxy-21- acetoXy-4-pregnene-3,20-dione, and then l6a-b10m0-17ochydroxy-Z1-acetoxy-4-pregnene-3,ZO-dione.

(d) 16oz(17a)-ox.ido-21 acetoxy 4-pregnene-3,11,20- trione [ibid., page 206] first 16,8-bromo-17a-hydroxy-21- acetoXy-4-pregnene-3,11,20-trione, and then 16m-bromo- 171x-hydroxy-21-acetoxy-4-pregnene-3,1 1,20-trione.

(e) 160L(l7uc)-0XiClO-21 acetoxy-4,9(11)pregnadiene- 3,20-dione [Heller et al., J. Org. Chem. 26, 504-4 (1961)] first 165-bromo-17a-hydrow-21-acetoxy-4,9 1 1 -pregnadiene-3,20-dione, then 16a-bromo-17u-hydroxy-21-acetoxy-4,9(11)-pregnadiene-3,20-dione.

Example 5 In the same manner given in the preceding Examples 1-3, other 16a(17u)-oxidopregnanes can be treated with hydrogen iodide to give the corresponding 16fi-iodo- 17a-pregnane and isomerized with Raney nickel in methanol, ethanol, tetrahydrofuran, ethylether or other organic solvents to give the corresponding 16oc-i0dO-17m-l1YdIOXY- pregnanes. In this manner there was obtained from:

(a) 3u-acetoxy-16m(17a)-oXidopregnane-11,20 dione [Percy Julian, Recent Progress in Hormone Research, vol. VI, Academic Press, Inc., publishers, New York, 1951, page 200] first 3a-acetoXy-16fl-iodo-17a-hydroxypregnane-11,20-dione and then 3u-acetoxy16a-iodo-17ahydroxypregnane-l 1,20-dione.

(b) 3fl-hydroxy-16a(17a)-oxido 4 pregnene-11,20- dione [Percy Julian, Recent Progress in Hormone Research, vol. VI, Academic Press, Inc., publishers, New York, 1951, page 200] first 3,6-hydroxy -16fi-iodo-17uhydroxy-4-pregnene-11,20-dione, and then 3fi-hydroxy- 16a-iodo-17a-hydroxy-4-pregnene-1 1,20-dione.

(c) 16a(17e)-oxido-21-acetoxy-4 pregnene 3,20-dione [ibid., page 201] first 16,8-iod0-l7u-hydroxy-2l-acetoXy-4-pIegnene-3,ZO-dione, and then 16u-iOdO-17a-hydroxy-21-acetoxy-4-pregnene-3,20-dione.

(d) 16a(17a) oxido-Z1-acetoxy-4-pregnene-3,11,20- trione [ibid., page 206] first 165-iodo-17a-hydroxy-21- S acetoXy-4-pregnene-3,l1,20-trione, and then l6oc-i0d0-l7ochydroXy-2 l-acetoXy-4-pregnene-3, 11,20-tri0ne.

(e) 16a(17a)-OXldO-21 acet0xy-4,9(11)-pregnadiene- 3,20-dione [Heller et al., J. Org. Chem. 26, 5044 (1961)] first 16/3-iodo-17a-hydroXy 21 acetoxy-4,9(11)-pregnadiene-3,20-dione, then 16a-iodo-17a-hydroxy-2l-acetoxy- 4,9 (1 1 -pregnadiene-3,20-di0ne.

I claim:

1. A process for the production of 160c-l13l0-17a-hY- droxypregnanes, wherein the halogen is selected from the group consisting of bromine and iodine, which comprises:

treating with 0.1 to 10 parts of active nickel catalyst one part of a 1GB-halo-17a-hydroxypregnane wherein the halogen is defined as above at a temperature between 0 and to obtain the corresponding 16oc-ha10-17cc-11YdIOXY- pregnane, wherein the halogen is defined as above.

2. A process for the production of 16u-halo-17a-hydroxypregnanes, wherein the halogen is selected from the group consisting of bromine and iodine, which comprises: treating with 0.5 to 3 parts of Raney nickel at a temperature between 0 and 125, one part of a 16B-halo-17ahydroxypregnane, wherein the halogen is defined as above, to obtain the corresponding 16a-halo-17a-hydroxypregnane.

3. A process for the production of 16a-halo-17u-hydroxypregnanes, wherein the halogen is selected from the group consisting of bromine and iodine, which comprises: treating with 0.5 to 3 parts of Raney nickel one part of a 16,8-halo-17u-hydroxypregnane, wherein the halogen is defined as above, in an organic solvent at a temperature between 0 and 125, to obtain the corresponding chalo- 1 7a-hydroxypregnane.

4. A process for the production of 16oz-halO-17cz-hY- droxypregnanes, wherein the halogen is selected from the group consisting of bromine and iodine, which comprises: treating in an inert gas atmosphere with 0.5 to 3 parts of Raney nickel one part of a 16fi-halo-17a-hydroxypregnane, wherein the halogen is defined as above, at a temperature between 0 and 125, to obtain the corresponding 16a-halo-17u-hydroxypregnane.

5. A process for the production of 16u-bromo-3fi,17mdihydroxy-6-methyl-5-pregnen-20 one which comprises: treating one part of 16fi-bromo-3fi,17a-dihydroXy-6-methyl-S-pregnen-ZO-one with 0.5 to 3 parts of Raney nickel, at a temperature between 0 and 125, to obtain 16a.- bromo-Bfi,l7a-dihydroxy-6-methyl-5-pregnen-20-one.

6. A process for the production of 16oc-iOdO-3B,17adihydroxy-6-methyl-5-pregnen-20 one which comprises: treating one part of 16,3-iodo-3fi,17oz-dihydroxy-6-methyl- 5-pregnen-20-one with 0.5 to 3 parts of Raney nickel, at a temperature between 0 and 125 to obtain 16a-i0d0- 3B,17u-dihydroxy-6-rnethyl-5-pregnen-20-one.

7. A process for the production of 16oc-bI'0mO-3fl,17a, 2l-trihydroxy-S-pregnen-Z0-one 3,21-diacetate which comprises: treating one part of 16B-bromo-3fi,17a,21-t1ihydroxy-S-pregnen-ZO-one 3,21-diacetate with 0.5 to 3 parts of Raney nickel, at a temperature between 0 and 125, to obtain 16u-bromo-3p,17a,2l-trihydroxy-S-pregnen-ZO- one 3,21-diacetate.

References Cited by the Examiner UNITED STATES PATENTS 3,022,295 2/ 62 Berg et a1. 260-23955 3,105,069 9/63 Komeno et al 260-23955 LEWIS GOTTS, Primary Examiner. 

1. A PROCESS FOR THE PRODUCTION OF 16A-HALO-17A-HYDROXPREGNANES, WHEREIN THE HALOGEN IS SELECTED FROM THE GROUP CONSISTING OF BROMINE AND IODINE, WHICH COMPRISES: TREATING WITH 0.1 TO 10 PARTS OF ACTIVE NICKEL CATALYST ONE PART OF A 16B-HALO-17A-HYDROXPREGNANE WHEREIN THE HALOGEN IS DEFINED AS ABOVE A TEMPERATURE BETWEEN 0* AND 125*, TO OBTAIN THE CORRESPONDING 16A-HALO-17A-HYDROXYPREGNANE, WHEREIN THE HALOGEN IS DEFINED AS ABOVE. 